Identification of polyoxometalates as nanomolar noncompetitive inhibitors of protein kinase CK2

Chem Biol. 2008 Jul 21;15(7):683-92. doi: 10.1016/j.chembiol.2008.05.018.

Abstract

Protein kinase CK2 is a multifunctional kinase of medical importance that is dysregulated in many cancers. In this study, polyoxometalates were identified as original CK2 inhibitors. [P2Mo18O62](6-) has the most potent activity. It inhibits the kinase in the nanomolar range by targeting key structural elements located outside the ATP- and peptide substrate-binding sites. Several polyoxometalate derivatives exhibit strong inhibitory efficiency, with IC50 values < or = 10 nM. Furthermore, these inorganic compounds show a striking specificity for CK2 when tested in a panel of 29 kinases. Therefore, polyoxometalates are effective CK2 inhibitors in terms of both efficiency and selectivity and represent nonclassical kinase inhibitors that interact with CK2 in a unique way. This binding mode may provide an exploitable mechanism for developing potent drugs with desirable properties, such as enhanced selectivity relative to ATP-mimetic inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / chemistry
  • Binding Sites
  • Casein Kinase II / antagonists & inhibitors*
  • Chemistry, Pharmaceutical / methods
  • Dose-Response Relationship, Drug
  • Drug Design
  • Drug Evaluation, Preclinical
  • Humans
  • Inhibitory Concentration 50
  • Molecular Conformation
  • Molecular Structure
  • Peptides / chemistry
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Structure-Activity Relationship
  • Tungsten Compounds / chemistry
  • Tungsten Compounds / pharmacology*

Substances

  • Peptides
  • Protein Kinase Inhibitors
  • Tungsten Compounds
  • polyoxometalate I
  • Adenosine Triphosphate
  • Casein Kinase II